Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among ...treatment effect, circulating nephritogenic anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m(2)) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximab-treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA2R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio HR, 7.90; 95% confidence interval 95% CI, 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA2R antibody depletion. On average, 50% anti-PLA2R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.
Rituximab in Idiopathic Membranous Nephropathy RUGGENENTI, Piero; CRAVEDI, Paolo; CHIANCA, Antonietta ...
Journal of the American Society of Nephrology,
08/2012, Letnik:
23, Številka:
8
Journal Article
Recenzirano
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Selective depletion of B cells with the mAb rituximab may benefit the autoimmune glomerular disease idiopathic membranous nephropathy (IMN). Here, we describe our experience treating 100 consecutive ...IMN patients with persistent nephrotic syndrome with rituximab. We defined complete remission as persistent proteinuria <0.3 g/24 h and partial remission as persistent proteinuria <3 g/24 h, each also having >50% reduction in proteinuria from baseline. During a median follow-up of 29 months after rituximab administration, 65 patients achieved complete or partial remission. The median time to remission was 7.1 months. All 24 patients who had at least 4 years of follow-up achieved complete or partial remission. Rates of remission were similar between patients with or without previous immunosuppressive treatment. Four patients died and four progressed to ESRD. Measured GFR increased by a mean 13.2 (SD 19.6) ml/min per 1.73 m(2) among those who achieved complete remission. Serum albumin significantly increased and albumin fractional clearance decreased among those achieving complete or partial remission. Proteinuria at baseline and the follow-up duration each independently predicted the decline of proteinuria. Furthermore, the magnitude of proteinuria reduction significantly correlated with slower GFR decline (P=0.0001). No treatment-related serious adverse events occurred. In summary, rituximab achieved disease remission and stabilized or improved renal function in a large cohort of high-risk patients with IMN.
To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate GFR ≥120 mL/min/1.73 m(2)), GFR decline, and nephropathy onset or progression in type 2 diabetic patients ...with normo- or microalbuminuria.
We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 μg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA(1c) was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively.
Over a median (range) follow-up of 4.0 (1.7-8.1) years, GFR declined by 3.37 (5.71-1.31) mL/min/1.73 m(2) per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: -0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 95% CI 1.13-4.14). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up.
Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.
Summary Background Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue ...octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. Methods We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m2 or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov , NCT00309283. Findings Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. Interpretation These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. Funding Polycystic Kidney Disease Foundation.
Implementing shortened one-compartment iohexol plasma clearance models for GFR measurement is crucial since the gold standard inulin renal clearance technique and the reference two-compartment, ...10-hour, 16-samplings iohexol plasma clearance method are clinically unfeasible. Inulin may precipitate anaphylactic shock. Four-hour and 8-hour one-compartment iohexol plasma clearance models with Bröchner-Mortensen correction provide accurate GFR measurements in patients with estimated GFR (eGFR) > or less than or equal to40 mL/min/1.73m.sup.2, respectively. We compared the performance of the simplified 5-hour, 4-samplings, two-compartment population pharmacokinetic model (popPK) with the performance of the reference two-compartment 10-hour iohexol method in 16 patients with GFR 15.2 to 56.5 mL/min/1.73 m.sup.2 . We also compared the performance of shortened (5, 6 and 7-hour) one-compartment models with the performance of the standard 8-hour one-compartment model in 101 patients with eGFR less than or equal to40 mL/min/1.73 m.sup.2 . The performance of popPK and shortened methods versus reference methods was evaluated by total deviation index (TDI), concordance correlation coefficient (CCC) and coverage probability (CP). TDI 90% indicated adequate performance. TDI, CCC and CP of popPK were 11.11%, 0.809 and 54.10%, respectively. All shortened, one-compartment models overestimated the GFR (p <0.0001 for all) as compared to the 8-hour model. TDI, CCC and CP were 7.02%, 0.815, and 75.80% for the 7-hour model, 7.26%, 0.803, and 74.20% for the 6-hour model, and 8.85%, 0.729 and 64.70% for the 5-hour model. The agreement of popPK model was comparable to that obtained with the Chronic-Kidney-Disease-Collaboration-Epidemiology (CKD-Epi) and the Modification-of-Diet-in-Renal-Disease (MDRD) serum-creatinine based equations for GFR estimation. PopPK model is remarkably unreliable for GFR measurement in stage III-IV CKD patients. In patients with eGFR less than or equal to40 mL/min/1.73m.sup.2, shortened one-compartment models, in particular the 5-hour model, are less performant than the reference 8-hour model. For accurate GFR measurements, the iohexol plasma clearance should be measured with appropriate protocols. Over-simplified procedures should be avoided.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is no simple method to measure glomerular filtration rate (GFR) in mice, which limits the use of mice in models of renal diseases. We aimed at simplifying the plasma clearance of iohexol in ...mice, using dried blood spot (DBS) sampling in order to reduce the amount of blood taken for analysis. GFR was measured simultaneously by a reference method in total blood-as described before-and tested method using DBS in fifteen male and six female C57BL/6J mice. Total blood extraction was 50 μL for the reference methods and 25μL for the tested methods, distributed in 5 samples. The agreement of GFR values between both methods was analyzed with the concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). The agreement between both methods was excellent, showing a TDI = 8.1%, which indicates that 90% of the GFR values obtained with DBS showed an error ranging from - 8 to + 8% of the reference method; a CCC of 0.996 (CI: 0.992), reflecting high precision and accuracy and a CP of 94 (CI: 83), indicating that 6% of the GFR values obtained with DBS had an error greater than 10% of the method in blood. So, both methods are interchangeable. DBS represent a major simplification of GFR measurement in mice. Also, DBS improves animal welfare by reducing the total blood required and refining the procedure.
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an ...additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF) and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE) inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal ...disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD.
We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15-40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 -0.63 to 1.75 ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio HR 95% CI adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 0.127 to 0.742, p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR 95% CI: 0.121 0.017 to 0.866, p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size.
In this study we observed that in later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4.
ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report here the long-term clinical and immunological results of four living-donor kidney transplant patients given autologous bone marrow-derived mesenchymal stromal cells (MSCs) as part of a ...phase 1 study focused on the safety and feasibility of this cell therapy. According to study protocols implemented over time, based on initial early safety findings, the patients were given MSC at day 7 posttransplant (
= 2) or at day -1 pretransplant (
= 2) and received induction therapy with basiliximab and low-dose rabbit anti-thymocyte globulin (RATG) or RATG alone, and were maintained on low-dose ciclosporin (CsA)/mycophenolate mofetil (MMF). All MSC-treated patients had stable graft function during the 5- to 7-year follow-up, without increased susceptibility to infections or neoplasm. In three MSC recipients, but not historical control patients, circulating memory CD8
T cell percentages remained lower than basal, coupled with persistent reduction of
donor-specific cytotoxicity. Two patients showed a long-lasting increase in the regulatory T cell/memory CD8
T cell ratio, paralleled by high circulating levels of naïve and transitional B cells. In one of these two patients, CsA was successfully discontinued, and currently the low-dose MMF monotherapy is on the tapering phase. The study shows that MSC therapy is safe in the long term and could promote a pro-tolerogenic environment in selected patients. Extensive immunomonitoring of MSC-treated kidney transplant recipients could help selection of patients for safe withdrawal of maintenance immunosuppressive drugs (NCT00752479 and NCT02012153).
Preventing Microalbuminuria in Type 2 Diabetes Ruggenenti, Piero; Fassi, Anna; Ilieva, Anelja Parvanova ...
New England journal of medicine/The New England journal of medicine,
11/2004, Letnik:
351, Številka:
19
Journal Article
Recenzirano
Odprti dostop
In a multicenter, double-blind, placebo-controlled, randomized study, subjects with type 2 diabetes mellitus and hypertension but normal urinary albumin levels were treated with an ...angiotensin-converting–enzyme (ACE) inhibitor (trandolapril) and a non-dihydropyridine calcium-channel blocker (verapamil) alone or in combination to investigate whether treatment could forestall the development of microalbuminuria, which heralds diabetic nephropathy. The use of trandolapril alone or with verapamil appeared to be effective, whereas verapamil alone was no better than placebo.
ACE inhibition may prevent or retard the development of microalbuminuria in patients with type 2 diabetes mellitus.
Type 2 diabetes mellitus is a public health concern, and projections of its future effect are alarming. According to the World Health Organization, diabetes affects more than 170 million people worldwide, and this number will rise to 370 million by 2030.
1
About one third of those affected will eventually have progressive deterioration of renal function.
2
The first clinical sign of renal dysfunction in patients with diabetes is generally microalbuminuria (a sign of endothelial dysfunction that is not necessarily confined to the kidney),
4
which develops in 2 to 5 percent of patients per year.
5
,
6
In type 2 diabetes, unlike type . . .
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